Clinical History:

A 24-year-old woman was found on the floor of her apartment by her mother. Next to her was a bottle labelled "Tylenol, extra strength" and "100 tablets" which was empty. The mother called paramedics who took her daughter to a local hospital. Laboratory data indicated increasing ALT and AST. She was started on dialysis. Despite therapy, she died a week later. Further history from the mother revealed that her daughter had recently gone through a divorce in which she had lost custody of her two children.

Image 7.1:

This is a low power microscopic view (H&E stain) of the liver. There are extensive patchy areas of necrosis.

Image 7.2:

A high power view of the liver is shown here. Many hepatocytes show necrosis (without evidence of a significant amount of inflammation. No infectious agents would be found.

Questions:

1. What is the diagnosis?

This is acetaminophen induced liver necrosis. The rising liver enzymes (AST and ALT) result from this necrosis and release of enzymes. Many drugs are toxic at high concentrations. That is why you carefully write out dosages in prescriptions.

Acetaminophen toxicity may actually have greater morbidity and mortality in cases of accidental overdose. This is because of the greater number of persons with an underlying risk factor of chronic alcoholism in cases of accidental overdose. Acetaminophen in small amounts is metabolized by hepatic conjugation with glucuronidation and sulfation. Following an acute ingestion of greater than 140 mg/kg of body weight, the normal metabolic pathways are overwhelmed and an increased amount of acetaminophen becomes metabolized to a toxic metabolite known as N-acetyl-p-benzoquinoneimine (NAPQI) by cytochrome P450. The NAPQI is normally detoxified by glutathione. However, chronic alcoholism (and malnutrition) depletes glutathione, and also induces P450 to increase toxicity. (Acute ethanol ingestion inhibits P450.) Thus, previous chronic alcohol ingestion increases the risk for acetaminophen toxicity.

2. What is the manner of death?

The evidence suggests a suicide.

3. What acute therapy is available?

N-acetylcysteine can be administered orally, based upon body weight. This agent probably works by maintaining or restoring hepatic glutathione levels, or by acting as an alternate substrate for conjugation with and detoxification of reactive metabolites.